Esimil Side Effects

Note: This page contains information about the side effects of guanethidine / hydrochlorothiazide. Some of the dosage forms included on this document may not apply to the brand name Esimil.

Applies to guanethidine / hydrochlorothiazide: oral tablet

Cardiovascular

The risk for orthostatic hypotension, sometimes followed by syncope, is greatest within the first 10 minutes after dosing, early in the morning, and in hypovolemic patients. It is accentuated by alcohol, hot weather, and exercise--all of which are associated with peripheral vasodilation. The manufacturer recommends that guanethidine-HCTZ be gradually withdrawn over at least two weeks prior to administration of general anesthetics to avoid cardiovascular collapse during induction.[Ref]

Cardiovascular side effects from guanethidine can result from excessive sympathetic blockade or a relative increase in parasympathetic tone. Orthostatic hypotension is reported in approximately 15% of patients. Some of these patients experience syncope.

Unopposed or excessive parasympathetic tone can cause excessive bradycardia in rare cases, which may lead to serious problems in patients with underlying sinus node dysfunction.

Guanethidine can cause generalized edema in 10% to 15% of patients, although it is less likely with the addition of HCTZ. Edema, should it occur, may be important in patients with preexisting congestive heart failure.

Arrhythmias, including ventricular ectopy and complete AV heart block, may be rarely associated with HCTZ-induced hypokalemia.[Ref]

Gastrointestinal

Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in an increased risk of cholesterol gallstone formation. Cases of bowel strictures associated with thiazide ingestion have been reported in the 1960's, although these patients were on a combination HCTZ-potassium product.[Ref]

Gastrointestinal side effects are also related to increased parasympathetic tone. Diarrhea is reported in 11% of patients, some of whom discontinue therapy because of it. Dry mouth or parotid tenderness are reported in approximately 5% of patients. Rare cases of pancreatitis and acute cholecystitis are associated with HCTZ.[Ref]

Metabolic

HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and VLDL lipoprotein cholesterol levels by 50%, as well as reduce insulin secretion. It should be used with caution in patients with diabetes or hypercholesterolemia. Indeed, hyperosmolar hyperglycemic coma has been associated with HCTZ.

HCTZ-induced hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may also occur, but are usually clinically insignificant except in malnourished patients.[Ref]

Metabolic side effects are commonly associated with HCTZ, especially when doses greater than 50 mg per day are used. Mild hypokalemia (decrease of 0.5 mEq/L) occurs in up to 50% of patients on HCTZ alone and may predispose patients to cardiac arrhythmias. Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, hypercholesterolemia, and hyperuricemia are also relatively common.[Ref]

Hypersensitivity

A 68-year-old man with a history of myocardial infarction (MI) developed dyspnea, chest tightness, a low grade fever, dizziness, sweating, and vomiting associated with cyanosis, a mild leukocytosis, radiographic evidence of pulmonary edema, clinical evidence of hypovolemia, and respiratory acidosis. MI and infection were ruled out. The patient recovered after restoration of his intravascular volume with saline and albumin. The only precipitating factor per history was the ingestion of HCTZ, which the patient had taken without incident for two years. Rechallenge resulted in recurrent acute pulmonary edema. Other signs of hypersensitivity, such as rash and eosinophilia, were absent.[Ref]

Hypersensitivity reactions are not associated with guanethidine; however, serious reactions, including acute pulmonary edema, interstitial cystitis, interstitial nephritis and anaphylaxis, have been associated with HCTZ in rare cases. Approximately 1% of patients on HCTZ develop a syndrome of nausea, vomiting, diarrhea, and rash.[Ref]

Dermatologic

A 67-year-old white woman with hypothyroidism, hypercalcemia, depression, and hypertension developed facial erythema, headaches, tremors, confusion, and personality changes associated with a new positive ANA and anti-nRNP, and skin biopsy consistent with lupus erythematosus while taking HCTZ, levothyroxine, and amitriptyline. The eruption resolved upon discontinuation of HCTZ, but she later developed a higher ANA titer associated with symptomatic diffuse interstitial pulmonary infiltrates. She was successfully treated with corticosteroids.[Ref]

Dermatologic reactions are associated with HCTZ but not guanethidine. Cases of erythema annular centrifugum, acute eczematous dermatitis, morbilliform and leukocytoclastic vasculitis have been reported. Thiazides may induce phototoxic dermatitis. In addition, a rare, distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus has been associated with HCTZ.[Ref]

Renal

Renal side effects including new or worsened renal insufficiency may occur due to HCTZ-induced intravascular volume depletion. Rare cases of interstitial nephritis have been associated with HCTZ. In one study of patients on guanethidine, 58% with or without preexisting elevated BUN developed an increase in the BUN. The study did not, however, quantify the rise in BUN, attempt to make an association with the degree of blood pressure control, or attempt to measure other parameters of renal function.[Ref]

Although HCTZ has been used to treat nephrogenic diabetes insipidus, a case in which the drug was believed to have caused this condition has been reported.[Ref]

Genitourinary

Genitourinary side effects including sexual impotence have been reported as relatively uncommon genitourinary complaints among patients taking guanethidine, occurring in only approximately 2% of male patients. Smaller studies, where specific questions were asked, revealed an incidence of impotence as high as 60% in male patients taking guanethidine. Delayed or retrograde ejaculation and decreased sperm counts have also been reported. Impotence appears to be invariably reversible upon discontinuation of therapy or reduction in dosage.[Ref]

There is evidence that guanethidine may interfere with ejaculation by inhibiting contraction of the seminal vesicle, ampula and ductus deferens.[Ref]

Respiratory

Respiratory side effects including nasal stuffiness is a relatively common respiratory complaint among patients taking guanethidine, reported in up to 30%. Rare cases of dyspnea on exertion unaccompanied by other signs or symptoms of congestive heart failure have been associated with guanethidine. Approximately 30 case reports of acute noncardiogenic pulmonary edema have been associated with HCTZ.[Ref]

Nervous system

Nervous system side effects are infrequently reported since guanethidine does not affect the central nervous system. Insomnia and weakness are occasionally reported more often with guanethidine than with placebo. A single case of cerebrovascular insufficiency has been associated with HCTZ-induced plasma volume contraction.[Ref]

Immunologic

There are rare case reports of HCTZ-induced immune hemolytic anemia. The following illustrates a fatal case:

A 53-year-old man with hypertension developed nausea, vomiting, diarrhea, and progressive anorexia and weakness associated with scleral icterus, anemia with spherocytosis, dark red urine with proteinuria, bilirubinuria, hemoglobinuria, and elevated serum lactic dehydrogenase levels 18 months after beginning HCTZ and methyldopa. Haptoglobin was less than 50 mg per dl. Direct and indirect Coombs tests were positive. The patient died suddenly. Autopsy revealed no obvious cause of death, left ventricular hypertrophy, and mild coronary atherosclerosis.[Ref]

Immunologic side effects are rare. Cases of allergic vasculitis and hemolytic anemia have been associated with HCTZ.[Ref]

Hematologic

Hematologic side effects are rare. Cases of immune-complex hemolytic anemia, aplastic anemia, and thrombocytopenia have been associated with HCTZ.[Ref]

Musculoskeletal

Endocrine

A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed an increased average fasting blood glucose level after treatment. Withdrawal of thiazide therapy for seven months in 10 of the patients resulted in average reductions of 10% in fasting blood glucose and 25% in the 2-hours glucose tolerance test values. A control group was not reported.[Ref]

Endocrinologic problems associated with thiazide diuretics include glucose intolerance and a potentially deleterious effect on the lipid profile, either of which may be important in some patients with or who are at risk for diabetes or coronary artery disease.[Ref]

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